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Original Article

Regulation of Interleukin (Il)-18 Receptor Chain Expression on Cd4⁺ T Cells during T Helper (Th)1/Th2 Differentiation

Ronald B. Smeltz^a, June Chen^a,b, Jane Hu-Li^a, and Ethan M. Shevach^a

^a Laboratory of Immunology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
^b Howard Hughes Medical Institute, National Institutes of Health Research Scholars Program, Bethesda, MD 20814
National Institutes of Health, Bldg. 10, Rm. 11N315, Bethesda, MD 20892.301-496-0222301-496-6449

ems1{at}mail.nih.gov

Interleukin (IL)-18 has been well characterized as a costimulatory factor for the induction of IL-12–mediated interferon (IFN)- production by T helper (Th)1 cells, but also can induce IL-4 production and thus facilitate the differentiation of Th2 cells. To determine the mechanisms by which IL-18 might regulate these diametrically distinct immune responses, we have analyzed the role of cytokines in the regulation of IL-18 receptor chain (IL-18R) expression. The majority of peripheral CD4⁺ T cells constitutively expressed the IL-18R. Upon antigen stimulation in the presence of IL-12, marked enhancement of IL-18R expression was observed. IL-12–mediated upregulation of IL-18R required IFN-. Activated CD4⁺ T cells that expressed low levels of IL-18R could produce IFN- when stimulated with the combination of IL-12 and IL-18, while CD4⁺ cells which expressed high levels of IL-18R could respond to IL-18 alone. In contrast, T cell stimulation in the presence of IL-4 resulted in a downregulation of IL-18R expression. Both IL-4^–/– and signal transducer and activator of transcription (Stat)6^–/– T cells expressed higher levels of IL-18R after TCR stimulation. Furthermore, activated T cells from Stat6^–/– mice produced more IFN- in response to IL-18 than wild-type controls. Thus, positive/negative regulation of the IL-18R by the major inductive cytokines (IL-12 and IL-4) determines the capacity of IL-18 to polarize an immune response.

Key Words: IFN-–inducing factor • IL-12 • IL-1R–related protein • Stat • IFN-

Abbreviations used in this paper: IL-18R, IL-18 receptor chain; MFI, mean fluorescence intensity; NMS, normal mouse serum; RAG, recombination activating gene; Stat, signal transducer and activator of transcription.

© 2001 The Rockefeller University Press

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